Tea domain transcription factor TEAD4 mitigates TGF-beta signaling and hepatocellular carcinoma progression independently of YAP

Tea domain transcription factor 4 (TEAD4) plays a pivotal role in tissue development and homeostasis by interacting with Yes-associated protein (YAP) in response to Hippo signaling inactivation. TEAD4 and YAP can also cooperate with transforming growth factor-beta (TGF-beta)-activated Smad proteins to regulate gene transcription. Yet, it remains unclear whether TEAD4 plays a YAP-independent role in TGF-beta signaling. Here, we unveil a novel tumor suppressive function of TEAD4 in liver cancer via mitigating TGF-beta signaling. Ectopic TEAD4 inhibited TGF-beta-induced signal transduction, Smad transcriptional activity, and target gene transcription, consequently suppressing hepatocellular carcinoma cell proliferation and migration in vitro and xenograft tumor growth in mice. Consistently, depletion of endogenous TEAD4 by siRNAs enhanced TGF-beta signaling in cancer cells. Mechanistically, TEAD4 associates with receptor-regulated Smads (Smad2/3) and Smad4 in the nucleus, thereby impairing the binding of Smad2/3 to the histone acetyltransferase p300. Intriguingly, these negative effects of TEAD4 on TGF-beta/Smad signaling are independent of YAP, as impairing the TEAD4-YAP interaction through point mutagenesis or depletion of YAP and/or its paralog TAZ has little effect. Together, these results unravel a novel function of TEAD4 in fine tuning TGF-beta signaling and liver cancer progression in a YAP-independent manner.

Automated summary

TEAD4 plays a pivotal role in tissue development and homeostasis by interacting with YAP. It also regulates gene transcription with TGF-beta-activated Smad proteins. This study reveals a novel tumor suppressive function of TEAD4 in liver cancer by mitigating TGF-beta signaling in a YAP-independent manner.